Synthesis of 3-aryl-2-[hydroxy(diaryl)methyl]-4-oxo-3,4-dihydroquinazolines

Article abstract of DOI:10.1134/S107042801011014X

By heating arylamides of N-ethoxalylanthranilic acid in the acetic acid mediun in the presence of triethylamine the corresponding ethyl 3-aryl-4-oxo-3,4-dihydroquinazoline-2-carboxylates were obtained. The latter in the conditions of the Grignard reaction formed 3-aryl-2-[hydroxy-(diaryl)methyl] -4-oxo-3,4-dihydroquinazolines. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S107042801011014X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 11, pp. 1687−1690. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, D.V. Levashov, K.M. Sytnik, L.M. Shemchuk, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 11, pp. 1680−1683.
Synthesis of 3-Aryl-2-[hydroxy(diaryl)methyl]-4-oxo-3,4-dihy-
droquinazolines
L. A. Shemchuk, V. P. Chernykh, D. V. Levashov, K. M. Sytnik, and L. M. Shemchuk
National Pharmaceutical University, Kharkov, 61002, Ukraine
e-mail: elmitro_dv@mail.ru
Received October 30, 2009
Abstract—By heating arylamides of N-ethoxalylanthranilic acid in the acetic acid mediun in the presence of
triethylamine the corresponding ethyl 3-aryl-4-oxo-3,4-dihydroquinazoline-2-carboxylates were obtained. The latter
in the conditions of the Grignard reaction formed 3-aryl-2-[hydroxy-(diaryl)methyl]-4-oxo-3,4-dihydroquinazolines.
DOI: 10.1134/S107042801011014X
Derivatives of 4-oxo-3,4-dihydroquinazoline are
known as a promising class of biologically active com-
pounds [1, 2]. The aim of our study was the prepara-
tion of 3-aryl-2-[hydroxy-(diaryl)methyl]-4-oxo-3,4-
dihydroquinazolines combining in a single molecule a
quinazoline heterocycle and the residue of benzilic acid,
two active pharmacophores. To fulfill this task we selected
two approaches. The first consisted in the acylation of
anthranilic acid arylamides with diarylchloroacetic acids
chlorides followed by the reaction products heterocycliza-
tion into quinazolinone derivatives. The second approach
utilizes the reaction of oxamic acid esters with arylmag-
nesium halides which are known to stop at the stage of
the formation of diarylglycolic acid amides[3]. Therefore
we planned proceeding from N-ethoxalylanthranilic acid
amides to obtain ethyl 3-aryl-4-oxo-3,4-dihydroquin-
azoline-2-carboxylates and to study their reaction with
Grignard reagents.
Initial anthranilamides II were obtained from aryl-
amines and isatoic anhydride I; the reaction was carried
out without solvent or in DMF by procedure [4]. The
acylation of amide IIa with diphenylchloroacetic acid
chloride provided diamide IIIa in a low yield (Scheme
1). Inasmuch as the diarylchloroacetic acid, chlorides
containing various substituents in the benzene ring are
difficultly available this method cannot provide a wide
range of diamides III. Yet the main disadvantage of the
first approach lies in the difficulties in the cyclization
of compounds III into the corresponding quinazolines
due evidently to steric reasons. Initial diamides III were
isolated at the attempt to carry out the cyclization by
boiling in the acetic anhydride in the presence of sodium
acetate, and also at heating in the highly boiling solvents
(ethylene glycol, diphenyl oxide).
The arylamides of diarylglycolic acids are known to
undergo cyclization in the conditions of the acidochromic
Scheme 1.
O
O
O
O
O
Ar
Ph
Ar Ph
Cl
Ar
N
RNH2
O
H2SO4
Cl
N
O
N
H
H
H
Ph
Ph
OH
NH
NH
N
H
NH2
Ph
O
Ph
O
IVa
IIa_IIc
IIIa
I
1687

SHEMCHUK et al.
1688
condensation. Diamides III in the presence of sulfuric
acid easily closed into the corresponding oxindoles IV,
but in contrast to the published data [5] we did not observe
the hydrolysis of the amide group. We avoided the de-
amination by using for the condensation lesser amount of
sulfuric acid than in the previously described procedure.
amidoesters V under the conditions described in [8]. We
also failed to attain the cyclization of obtained compounds
V with the use of the other common procedures with plau-
sible result:At heating in high boiling solvents (diphenyl
oxide, ethylene glycol) cyclic product VI formed in a low
yield; in acetic anhydride the reaction did not occur, and
at adding sodium acetate a mixture formed of cyclic VI
and acyclic V compounds as showed the data of 1H NMR.
We remarked that in the acylation of anthranilamides II
with ethoxalyl chloride in acetic acid in the presence of
triethylamine alongside the ethoxalylation formed also
quinazoline VI. We attempted to carry out the cycliza-
tion of amidoesters V under analogous conditions; the
short heating of the latter in acetic acid medium in the
presence of a double excess of triethylamine furnished
quinazolinones VI in high yields.
The second way (Scheme 2) presumed the preparation
of the target 3-aryl-2-(diarylhydroxymethyl)-4-oxo-3,4-
dihydroquinazolines VII from ethyl 3-aryl-4-oxo-3,4-
dihydro-2-quinazolinecarboxylates. It is known that
alkylamides and also hydrazides [6] and hydroxamides of
the anthranilic acid [7] reacting with ethoxalyl chloride or
with diethyl oxalate readily close into the corresponding
ethyl 3-R-4-oxo-3,4-dihydroquinazoline-2-carboxylates;
at the same time in the case of arylamides the closure
of the quinazoline ring requires additional activation
[8]. After acylation anthranilamides II with ethoxalyl
chloride a mixture was isolated of quinazoline VI and
acyclic amidoester V. The reaction of amides II with
diethyl oxalate resulted only in acyclic arylamides of N-
ethoxalylanthranilic acid V.Asynthesis was described [8]
of initial quinazolines VI we required by the cyclization
of 2-N-ethoxalylanthranilamides (V) by treatment with
phosphorus trichloride or by heating in diethyl oxalate.
However we failed to obtain pure quinazolinone VI from
The procedures of the synthesis of quinazolinones
VI were developed by an example of ethyl 3-phenyl-
4-oxo-3,4-dihydroquinazoline-2-carboxylate (VIa). It
was reported previously that this compound melted at
108–109°C [8]. According to our data the melting point
of pure compound VIa is 96°C, and the mixture that we
have obtained at the acylation of amide IIa with ethoxa-
lyl chloride and containing cyclic VIa and acyclic Va
products melted at 109°C.
Scheme 2.
O
O
N
COCl
Ar
Ar
CO2Et
N
N
+
H
Et3N, AcOH
NHCOCO2Et
Vа_Vc
CO2Et
VIа_VIc
IIa_IIc
Et3N
AcOH
(CO2Et)2
Ar'MgHlg
Vа_Vc
III
Scheme 3.
R
O
O
Ar
N
H2SO4
Ar'MgHlg
N
VIа, VIb, VIc
Ar'
N
Ar'
N
Ar'
HO
VIIа_VIIf
Ar'
VIII
Ar = Ar' = Ph (a); Ar = 4-MeC6H4, Ar' = Ph (b); Ar = 2-MeOC6H4, Ar' = Ph (c); Ar = Ph, Ar' = 4-MeC6H4 (d); Ar = Ar' =
4-MeC6H4 (e); Ar = 2-MeOC6H4, Ar' = 4-MeC6H4 (f).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SYNTHESIS OF 3-ARYL-2-[HYDROXY(DIARYL)METHYL]-4-OXO-3,4-DIHYDROQUINAZOLINES
1689
Ethyl 2-(phenylcarbamoyl)phenylcarbamoyl-
methanoate (Va). In 4.2 ml (0.03 mol) of diethyl oxalate
2.12 g (0.01 mol) of amide IIa was heated for 30 min.
On cooling 5 ml of ethanol was added, the separated
precipitate was filtered off, dried, and recrystellized
from ethanol. Yield 2.50 g (80%), mp 155°С. 1Н NMR
spectrum, δ, ppm: 1.20 t (3H, CH3), 4.20 q (2Н, СН2),
7.10 t (1H, Ar), 7.30 m (3H, Ar), 7.60 m (3H, Ar), 7.90 d
(1H, Ar), 8.40 d (1H, Ar), 10.50 s (1H, NHPh), 12.00 s
(1H, NHCO). Found, %: C 65.36; H 5.18; N 8.98.
C17H16N2O4. Calculated, % : C 65.37; H 5.17; N 8.97.
We developed based on compounds V an effective
synthesis of amides III with various substituents in the
benzene ring. The readiness of the amidoesters V to
react with arylmagnesium halides and high yields of the
products suggest the use of this method as preparative.
Target 3-aryl-2-[hydroxy(diaryl)methyl]-4-oxo-3,4-
dihydroquinazolines VII were obtained in up to 85% yield
by treating with arylmagnesium halides quinazolinones
VI (Scheme 3). The reaction occurred exclusively at the
ester group, and even the five-fold excess of the reagent
did not affect the result of the reaction.
The obtained compounds VIIa–VIIf did not enter into
the acidochromic condensation apparently due to steric
hindrances.
Compounds Vb and Vc were similarly obtained.
Ethyl 2-(p-methylphenylcarbamoyl)phenyl-
ethanolmethanoate (Vb). Yield 2.45 g (75 %), mp
1
200°С. Н NMR spectrum, δ, ppm: 1.20 t (3H, CH3),
EXPERIMENTAL
2.20 s (3H, п-CH3), 4.20 q (2Н, СН2), 7.10 t (1H, Ar),
7.30 m (2H,Ar), 7.60 m (3H,Ar), 7.90 d (1H,Ar), 8.40 d
(1H, Ar), 10.50 s (1H, NHPh), 12.00 s (1H, NHCO).
Found, %: C 66.24; H 5.58; N 8.60. C18H18N2O4.
Calculated, % : C 66.24; H 5.57; N 8.59.
1Н NMR spectra were measured on a spectrometer
Varian M-200 (200 MHz) from solutions in DMSO-d6,
internal reference TMS. Elemental analysis was
performed on an analyzer Carlo Erba CHNS-O EA1108.
2-Amino-N-arylbenzamides IIa–IIc were obtained
from isatoic anhydride and substituted anilines by
procedure [4].
Ethyl 2-(o-methoxyphenylcarbamoyl)
phenylethanolmethanoate (Vc). Yield 3.08 g (90 %), mp
185°С. 1Н NMR spectrum, δ, ppm: 1.20 t (3H, CH3), 3.80
s (3H, OCH3), 4.20 q (2Н, СН2), 7.10 t (1H, Ar), 7.30 m
(2H, Ar), 7.60 m (3H, Ar), 7.90 d (1H, Ar), 8.40 d (1H,
Ar), 10.50 s (1H, NHPh), 12.00 s (1H, NHCO). Found,
%: C 63.13; H 5.30; N 8.17. C18H18N2O5. Calculated, %
: C 63.14; H 5.31; N 8.18.
2-Hydroxy(diphenyl)methylcarboxamido-N-
phenylbenzamide (IIIа). Asolution of 3.15 g (0.01 mol)
of ester Vа in 50 ml of freshly distilled THF was added
dropwise to the solution of phenylmagnesium bromide
in 50 ml of THF obtained by procedure [9] from 1.06 g
(0.04 mol) of magnesium and 4.04 ml (0.04 mol) of
phenyl bromide. The mixture was stirred for 1 h, 300 ml
of the saturated solution of ammonium chloride was
added, the organic layer was separated and evaporated,
the residue was recrystallized from methanol. Yield 3.38 g
Ethyl 4-oxo-3-phenyl-3,4-dihydroquinazoline-
2-carboxylate (VIa). A solution of 2.98 g (0.01 mol)
of ester Va and 2.8 ml (0.02 mol) of triethylamine in
25 ml of acetic acid was boiled for 40 min. On cooling
water was added, the separated precipitate was filtered
off, dried, and recrystallized from ethanol. Yield 2.65 g
(90 %), mp 95°С. 1Н NMR spectrum, δ, ppm: 0.90 t (3H,
CH3), 3.90 q (2H, CH2), 7.40 m (5H, Ph), 7.60 t (1H, H6),
7.80 d (1Н, Н8), 7.90 t (1Н, Н7), 8.20 d (1Н, Н5). Found,
%: C 69.37; H 4.81; N 9.51. C17H14N2O3. Calculated, %:
C 69.37; H 4.80; N 9.52.
1
(80%), mp 240°С. Н NMR spectrum, δ, ppm: 7.20 m
(16Н, Ar, OH), 7.90 m (3H, Ar), 8.50 d (1H, Ar) 10.50 s
(1H, NHPh), 11.80 s (1H, NHCO). Found, %: C 76.76;
H 5.57; N 6.63. C27H22N2O3. Calculated, % : C 76.75;
H 5.26; N 6.63.
2-Oxo-N,3,3-triphenylindoline-7-carboxamide
(IVa). To a solution of 4.04 g (0,01 mol) of amide IIIа
in 100 ml of acetic acid was added ~30 ml of concn.
H2SO4 till the end of appearance of red-brown color, the
mixture was poured into 300 ml of water, the precipitate
was filtered off and crystallized from ethanol. Yield 2.83 g
Compounds VIb and VIc were similarly obtained.
Ethyl 3-(p-methylphenyl)-4-oxo-3,4-dihydro-
quinazoline-2-carboxylate (VIb). Yield 2.62 g (85 %),
mp 100°С. 1Н NMR spectrum, δ, ppm: 0.90 t (3H, CH3),
2.40 s (3Н, п-СН3), 4.00 q (2H, CH2), 7.40 m (4H,
С6Н4), 7.60 t (1H, H6), 7.80 d (1Н, Н8), 7.90 t (1Н, Н7),
8.20 d (1Н, Н5). Found, %: C 70.10; H 5.23; N 9.09.
C18H16N2O3. Calculated, % : C 70.11; H 5.24; N 9.09.
1
(70%), mp 205°С. Н NMR spectrum, δ, ppm: 7.20 m
(16Н, Ar), 8.00 d (1H, Ar), 8.50 d (1H, Ar), 10.20 s
(1H, NHPh), 12.40 s (1H, NHCO). Found, %: C 80.16;
H 4.98; N 6.92. C27H20N2O2. Calculated, % : C 80.17;
H 4.99; N 6.93.
Ethyl 3-(o-methoxyphenyl)-4-oxo-3,4-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SHEMCHUK et al.
1690
phenyl-3,4-dihydroquinazoline (VIId). Yield 3.03 g
(70%), mp 185°С. 1Н NMR spectrum, δ, ppm: 2.10 s (6H,
CH3), 7.20–7.40 m (14H, Ar, OH), 7.60 m (2H, H6,8),
8.20 t (1Н, Н7), 8.40 d (1Н, Н5). Found, %: C 80.51;
H 5.60; N 6.47. C29H24N2O2. Calculated, % : C 80.52;
H 5.60; N 6.48.
dihydroquinazoline-2-carboxylate (VIc). Yield 3.08 g
(95 %), mp 130°С. 1Н NMR spectrum, δ, ppm: 0.90 t (3H,
CH3), 3.80 s (3Н, OСН3), 4.00 q (2H, CH2), 6.80 t (1Н,
Ar), 7.00 d (1Н, Ar), 7.40 m (2H, Ar), 7.60 t (1H, H6),
7.80 d (1Н, Н8), 7.90 t (1Н, Н7), 8.20 d (1Н, Н5). Found,
%: C 66.64; H 4.97; N 8.64. C18H16N2O4. Calculated, %:
C 66.65; H 4.98; N 8.64.
2-[Hydroxy-bis(p-methylphenyl)methyl]-3-(p-
methylphenyl)-4-oxo-3,4-dihydroquinazoline (VIIe).
Yield 3.25 g (75%), mp 145°С. Н NMR spectrum, δ,
2-[Hydroxy(diphenyl)methyl]-4-oxo-3-phenyl-
3,4-dihydroquinazoline (VIIa). A solution of 2.62 g
(0.01 mol) of ester VIa in 50 ml of freshly distilled THF
was added dropwise to the solution of phenylmagnesium
bromide in 50 ml of THF obtained by procedure [9] from
1.06 g (0.04 mol) of magnesium and 4.04 ml (0.04 mol) of
phenyl bromide.After the addition of the Grignard reagent
the reaction mixture turned brown-gray. It was stirred with
a magnetic stirrer for 1 h, 300 ml of a saturated solution
of ammonium chloride was added, the organic layer was
separated and evaporated. The residue was recrystallized
from methanol. Yield 3.03 g (75%), mp 207°С. 1Н NMR
spectrum, δ, ppm: 6.60 m (3H, Ar), 6.90 m (2H, Ar),
7.20 m (11H, Ar, OH), 7.60 m (2H, H6,8), 7.90 t (1Н,
Н7), 8.20 d (1Н, Н5). Found, %: C 80.16; H 5.00; N 6.93.
C27H20N2O2. Calculated, % : C 80.17; H 4.99; N 6.93.
1
ppm: 2.10 s (6H, CH3), 2.30 s (3H, CH3), 7.20-7.40 m
(11H, Ar, OH), 7.60 m (2H, Ar), 7.80 m (2H, H6,8), 8.20 t
(1Н, Н7), 8.40 d (1Н, Н5). Found, %: C 80.67; H 5.87;
N 6.26. C30H26N2O2. Calculated, % : C 80.68; H 5.88;
N 6.27.
2-[Hydroxy-bis(p-methylphenyl)methyl]-3-(o-
methoxyphenyl)-4-oxo-3,4-dihydroquinazoline (VIIf).
1
Yield 3.93 g (85%), mp 175°С. Н NMR spectrum, δ,
ppm: 2.20 s (6H, CH3), 3.20 s (3H, OMe), 6.50 d (1H,
Ar), 6.60 d (1H, Ar), 6.70 d (1H, Ar), 7.20 m (5H, Ar,
OH), 7.3 m (4H, Ar), 7.50 m (2H, H6,8), 7.70 t (1Н, Н7),
8.20 d (1Н, Н5). Found, %: C 77.88; H 5.68; N 6.05.
C30H26N2O3. Calculated, % : C 77.89; H 5.68; N 6.06.
REFERENCES
Compounds VIIb–VIIf were similarly obtained.
2-[Hydroxy(diphenyl)methyl]-3-(p-methylphenyl)-
4-oxo-3,4-dihydroquinazoline (VIIb). Yield 2.93 g
(70%), mp 198°С. 1Н NMR spectrum, δ, ppm: 2.20 s (3H,
CH3), 6.80 m (2H,Ar), 7.20 m (9H,Ar), 7.40–7.60 m (8H,
Ar, OH). Found, %: C 80.34; H 5.30; N 6.70. C28H22N2O2.
Calculated, % : C 80.35; H 5.31; N 6.70.
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cow: Izd. Novaya Volna, 2002, vol. 1, p. 540.
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hedron, 2001, p. 6671.
3. Petyunin, P.A., Sukhomlinov, A.K., and Panferova, N.G.,
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4. Cortez, R., Rivero, I. A., Somanathan, R., Aguirre, G.,
Ramirez, F., and Hong, E., Synth. Commun., 1991, p. 285.
5. Petyunin, P.A. and Panferova, N.G., Khim. Geterotsikl.
Soedin., 1972, p. 182.
6. Shemchuk, L.A., Chernykh, V.P., Arzumanov, P.S., and
Krys'kiv, O.S., Zh. Org. Khim., 2007, vol. 43, p. 724.
7. Shemchuk, L.A., Chernykh, V.P., and Krys’kiv, O.S., Zh.
Org. Khim., 2006, vol. 42, p. 395.
2-[Hydroxy(diphenyl)methyl]-3-(o-methoxy-
phenyl)-4-oxo-3,4-dihydroquinazoline (VIIc). Yield
3.69 g (85%), mp 145°С. Н NMR spectrum, δ, ppm:
3.20 s (3H, OMe), 6.50 d (1H, Ar), 6.60 m (2H, Ar),
6.70 d (1H, Ar), 7.20–7.30 m (11H, Ar, OH), 7.50 m
(2H, H6,8), 7.70 t (1Н, Н7), 8.20 d (1Н, Н5). Found, %:
C 77.40; H 5.11; N 6.46. C28H22N2O3. Calculated, % :
C 77.39; H 5.11; N 6.45.
1
8. Petyunin, P.A., Chernykh, V.P., Petyunin, G.P., and Ko-
zhevnikov, Yu.V., Khim. Geterotsikl. Soedin., 1970, p. 1575.
2-[Hydroxy-bis(p-methylphenyl)methyl]-4-oxo-3-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010